The Human T-cell Leukemia Virus type I basic leucine zipper factor upregulates the expression of the antioxidant Heme Oxygenase I,

Adult T-cell Leukemia/Lymphoma (ATLL) is a resilient lymphoproliferative disease of CD4+ T-cells infected by the Human T-cell Leukemia Virus type I (HTLV-1), for which there are no effective treatments. Mounting evidence supports that the overexpression of antioxidants contributes to drug resistance in many types of cancer. One such antioxidant is the iron-recycling enzyme Heme Oxygenase (HMOX-1), which has been shown to enhance cancer cell survival upon exposure to stress-inducing agents. HMOX-1 expression is regulated by the small Maf AP1 proteins, which control transcription from promoter antioxidant response elements (AREs). A previous report, confirmed by our laboratory, shows that the HTLV-1 antisense-encoded basic leucine zipper factor, HBZ, interacts with small Mafs for recruitment to AREs in vitro. We questioned whether HBZ and small Mafs regulate the expression of antioxidants like HMOX-1 as a pro-survival strategy in ATLL cells. Our results show that HMOX-1 is overexpressed in ATLL cells in a manner dependent upon both HBZ and the small Mafs. These proteins were found to be present at an ARE in the promoter of HMOX-1 in vivo, and HBZ expression was observed to promote ARE transactivation in a small Maf-dependent manner. HMOX-1 is thought to be the main mediator of iron metabolism and functions in a cytoprotective capacity during oxidative stress. We observed that ATLL cells, as well as HBZ-expressing cells, exhibited resistance to iron-induced cytotoxicity, which was attenuated upon inhibition of HMOX-1 enzyme activity. Furthermore, HBZ expression was found to be important for maintaining ATLL cell redox state, as well as for maintaining cell viability in response to iron exposure. These findings support the possibility that HBZ and small Mafs may upregulate transcription at AREs to positively regulate some antioxidant response genes in ATLL cells, wherein these gene products may have cytoprotective effects in response to oxidative stress and may contribute to anti-cancer drug resistance.ECU Research and Creative Achievement Wee

Seed system security assessment : Southern Sudan : November-December 2010

Juba, South Suda

Incentive payments are not related to expected health gain in the pay for performance scheme for UK primary care: cross-sectional analysis

Background: The General Medical Services primary care contract for the United Kingdom financially rewards performance in 19 clinical areas, through the Quality and Outcomes Framework. Little is known about how best to determine the size of financial incentives in pay for performance schemes. Our aim was to test the hypothesis that performance indicators with larger population health benefits receive larger financial incentives. Methods: We performed cross sectional analyses to quantify associations between the size of financial incentives and expected health gain in the 2004 and 2006 versions of the Quality and Outcomes Framework. We used non-parametric two-sided Spearman rank correlation tests. Health gain was measured in expected lives saved in one year and in quality adjusted life years. For each quality indicator in an average sized general practice we tested for associations first, between the marginal increase in payment and the health gain resulting from a one percent point improvement in performance and second, between total payment and the health gain at the performance threshold for maximum payment. Results: Evidence for lives saved or quality adjusted life years gained was found for 28 indicators accounting for 41% of the total incentive payments. No statistically significant associations were found between the expected health gain and incentive gained from a marginal 1% increase in performance in either the 2004 or 2006 version of the Quality and Outcomes Framework. In addition no associations were found between the size of financial payment for achievement of an indicator and the expected health gain at the performance threshold for maximum payment measured in lives saved or quality adjusted life years. Conclusions: In this subgroup of indicators the financial incentives were not aligned to maximise health gain. This disconnection between incentive and expected health gain risks supporting clinical activities that are only marginally effective, at the expense of more effective activities receiving lower incentives. When designing pay for performance programmes decisions about the size of the financial incentive attached to an indicator should be informed by information on the health gain to be expected from that indicator

Distinctive Patterns of MicroRNA Expression Associated with Karyotype in Acute Myeloid Leukaemia

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults; however, the genetic aetiology of the disease is not yet fully understood. A quantitative expression profile analysis of 157 mature miRNAs was performed on 100 AML patients representing the spectrum of known karyotypes common in AML. The principle observation reported here is that AMLs bearing a t(15;17) translocation had a distinctive signature throughout the whole set of genes, including the up regulation of a subset of miRNAs located in the human 14q32 imprinted domain. The set included miR-127, miR-154, miR-154*, miR-299, miR-323, miR-368, and miR-370. Furthermore, specific subsets of miRNAs were identified that provided molecular signatures characteristic of the major translocation-mediated gene fusion events in AML. Analysis of variance showed the significant deregulation of 33 miRNAs across the leukaemic set with respect to bone marrow from healthy donors. Fluorescent in situ hybridisation analysis using miRNA-specific locked nucleic acid (LNA) probes on cryopreserved patient cells confirmed the results obtained by real-time PCR. This study, conducted on about a fifth of the miRNAs currently reported in the Sanger database (microrna.sanger.ac.uk), demonstrates the potential for using miRNA expression to sub-classify cancer and suggests a role in the aetiology of leukaemia

Cross-cutting principles for planetary health education

Since the 2015 launch of the Rockefeller Foundation Lancet Commission on planetary health,1 an enormous groundswell of interest in planetary health education has emerged across many disciplines, institutions, and geographical regions. Advancing these global efforts in planetary health education will equip the next generation of scholars to address crucial questions in this emerging field and support the development of a community of practice. To provide a foundation for the growing interest and efforts in this field, the Planetary Health Alliance has facilitated the first attempt to create a set of principles for planetary health education that intersect education at all levels, across all scales, and in all regions of the world—ie, a set of cross-cutting principles

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial